ACS Medicinal Chemistry Letters最新文献

Heterocyclic peptidomimetics are constrained compounds that mimic the biological efficacy of peptides while offering increased stability. We have previously generated a diazaheterocyclic peripherally selective, mixed-opioid agonist peptidomimetic that produced synergistic antinociception with decreased side effects. Working from two earlier templates, we report here the synthesis of 15 new diazaheterocyclic analogues. In vitro screening with radioligand competition binding assays and [³⁵S]GTPγS assays demonstrated variable affinity for and activity at μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with three (2663-48, 2638-28 and 2638-33) displaying good affinity for DOR and/or KOR. All three compounds produced dose-dependent, opioid-receptor mediated antinociception in the mouse 55 °C warm-water tail-withdrawal and acetic-acid writhing assay, although a ratio of ED₅₀ values in these assays suggested poor BBB penetration by 2638-33; results confirmed by testing with naloxone-methiodide. The data suggest these diazaheterocyclic mixed-activity, peripherally restricted opioid receptor agonists may hold potential as new, safer analgesics.

Heterocyclic peptidomimetics are constrained compounds that mimic the biological efficacy of peptides while offering increased stability. We have previously generated a diazaheterocyclic peripherally selective, mixed-opioid agonist peptidomimetic that produced synergistic antinociception with decreased side effects. Working from two earlier templates, we report here the synthesis of 15 new diazaheterocyclic analogues. In vitro screening with radioligand competition binding assays and [³⁵S]GTPγS assays demonstrated variable affinity for and activity at μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with three (2663-48, 2638-28 and 2638-33) displaying good affinity for DOR and/or KOR. All three compounds produced dose-dependent, opioid-receptor mediated antinociception in the mouse 55 °C warm-water tail-withdrawal and acetic-acid writhing assay, although a ratio of ED₅₀ values in these assays suggested poor BBB penetration by 2638-33; results confirmed by testing with naloxone-methiodide. The data suggest these diazaheterocyclic mixed-activity, peripherally restricted opioid receptor agonists may hold potential as new, safer analgesics.

Targeted protein degradation has become the most pursued alternative modality to small-molecule inhibition over the past decade. The traditional strategy of blocking protein activity by tightly binding to a functional substrate pocket has progressed toward proteolysis-targeting chimeras (PROTACs), bivalent molecules that induce the knockdown of targeted proteins. Herein, a combined protocol is described for modeling ternary complexes via well-established approaches. We performed local protein-protein docking using Rosetta protocol and sampled the conformational landscape of a specific PROTAC molecule that was compatible with the generated protein-protein docking poses, followed by double and independent single-linkage/nearest-neighbor clustering for representative selection. Subsequently, we combined the fragment molecular orbital and density functional tight-binding methods to facilitate fast quantum mechanics-based energy calculations of the clustered ternary complexes. Finally, the computed energy values were utilized to score and select the best ternary poses, achieving good agreement with available crystallographic data.

Researchers have long recognized RAS mutations as one of the most challenging targets in oncology. These genetic alterations are central drivers of tumor progression in cancers such as melanoma, colorectal cancer, and pancreatic adenocarcinoma. The recent advancements described in patent applications WO 2024/243186 A2 and WO 2024/246099 A1 introduce two novel classes of inhibitors: heterocyclic compounds targeting NRAS G12D and spirocyclic derivatives directed at KRAS mutations, including G12C, G12D, and G12 V. These compounds, a fresh and innovative approach, disrupt critical RAS-dependent signaling pathways, offering a pathway to mitigate tumor growth and overcome resistance to standard therapies. This Patent Highlight explores their mechanisms, preclinical successes, and implications for future cancer treatment strategies.

The development of targeted protein degraders offers novel strategies for treating cancer and chronic viral infections. This Patent Highlight integrates bifunctional degraders, leveraging autophagy via p62, and substituted oxazolone compounds targeting IKZF1–4 transcription factors. These compounds demonstrate exceptional efficacy in degrading pathogenic proteins, reprogramming immune responses, and facilitating tumor immunity. This dual approach underscores the potential of cellular degradation systems in precision medicine.

Integrating advanced pharmaceutical innovations and artificial intelligence (AI) offers transformative potential for psychiatric care. This Patent Highlight reviews novel therapeutic strategies, including the synergistic use of monoamine antidepressants and short-duration psychedelics, alongside AI-driven behavioral efficacy tracking. The combination of selective serotonin reuptake inhibitors (SSRIs) with short-acting psychedelics, such as N,N-dimethyltryptamine (DMT) and psilocybin, provides rapid and sustained improvements in treatment-resistant depression and anxiety. Meanwhile, AI-enhanced behavioral monitoring leverages motion tracking and machine learning to quantify treatment outcomes in animal models, accelerating drug development. Together, these approaches redefine therapeutic paradigms, offering personalized and effective treatments for psychiatric disorders.